Medical cannabis

Medical cannabis (or medical marijuana) refers to the use of cannabis and its constituent cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), as medical therapy to treat disease or alleviate symptoms. The Cannabis plant has a history of medicinal use dating back thousands of years across many cultures.[1] Its usage in modern times is controversial, and in recent years the American Medical Association, the MMA, the American Society of Addiction Medicine, and other medical organizations have issued statements opposing its usage for medicinal purposes.[2][3][4]

Cannabis has been used to reduce nausea and vomiting in chemotherapy and people with AIDS, and to treat pain and muscle spasticity;[5] its use for other medical applications has been studied, but there is insufficient data for conclusions about safety and efficacy. Short-term use increases minor adverse effects, but does not appear to increase major adverse effects.[6]Long-term effects of cannabis are not clear,[6] and there are safety concerns including memory and cognition problems, risk for dependence and the risk of children taking it by accident.[5]

Medical uses

Cannabis as illustrated in Köhler's book of medicinal plants from 1897

Medical cannabis has several potential beneficial effects.[8][9] Cannabinoids can serve as appetite stimulants, antiemetics, antispasmodics, and have some analgesic effects,[1] may be helpful treating chronic non-cancerous pain, or vomiting and nausea caused by chemotherapy. The drug may also aid in treating symptoms of AIDS patients.[citation needed]

The U.S. Food and Drug Administration (FDA) has not approved smoked cannabis for any condition or disease as it deems evidence is lacking concerning safety and efficacy of cannabis for medical use.[10] The FDA issued an 2006 advisory against smoked medical cannabis stating: "marijuana has a high potential for abuse, has no currently accepted medical use in treatment in the United States, and has a lack of accepted safety for use under medical supervision."[10] The National Institute on Drug Abuse (NIDA) states that "Marijuana itself is an unlikely medication candidate for several reasons: (1) it is an unpurified plant containing numerous chemicals with unknown health effects; (2) it is typically consumed by smoking further contributing to potential adverse effects; and (3) its cognitive impairing effects may limit its utility".[11]

The Institute of Medicine, run by the United States National Academy of Sciences, conducted a comprehensive study in 1999[dated info] assessing the potential health benefits of cannabis and its constituent cannabinoids. The study concluded that smoking cannabis is not to be recommended for the treatment of any disease condition, but that nausea, appetite loss, pain and anxiety can all be mitigated by cannabis. While the study expressed reservations about smoked cannabis due to the health risks associated with smoking, the study team concluded that until another mode of ingestion was perfected providing the same relief as smoked cannabis, there was no alternative. In addition, the study pointed out the inherent difficulty in marketing a non-patentable herb, as pharmaceutical companies will likely make smaller investments in product development if the result is not patentable. The Institute of Medicine stated that there is little future in smoked cannabis as a medically approved medication, while in the report also concluding that for certain patients, such as the terminally ill or those with debilitating symptoms, the long-term risks are not of great concern.[12][13] Citing "the dangers of cannabis and the lack of clinical research supporting its medicinal value" the American Society of Addiction Medicine in March 2011 issued a white paper recommending a halt on use of marijuana as medication in the U.S., even in states where it had been declared legal.[14][15]

A 2010 Cochrane review said that cannabinoids were "probably effective" in treating chemotherapy-induced nausea in children, but with a high side effect profile (mainly drowsiness, dizziness, altered moods, and increased appetite). Less common side effects were "occular problems, orthostatic hypotension, muscle twitching, pruritis, vagueness, hallucinations, lightheadedness and dry mouth".[20]

HIV/AIDS

Evidence is lacking for both efficacy and safety of cannabis and cannabinoids in treating patients with HIV/AIDS or for anorexia associated with AIDS. As of 2013, current studies suffer from effects of bias, small sample size, and lack of long-term data.[21]

Pain

Cannabis appears to be somewhat effective for the treatment of chronic pain, including pain caused by neuropathy and possibly also that due to fibromyalgia and rheumatoid arthritis.[22][23] A 2009 review states it was unclear if the benefits were greater than the risks,[22] while a 2011 review considered it generally safe for this use.[23] In palliative care the use appears safer than that of opioids.[24]

Neurological problems

The use of cannabis in neurological problems, including multiple sclerosis, epilepsy, and movement problems, is not very clear.[25] Studies of the efficacy of cannabis for treating multiple sclerosis have produced varying results. The combination of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) extracts give subjective relief of spasticity, though objective post-treatment assessments do not reveal significant changes.[26] A trial of cannabis is deemed to be a reasonable option if other treatments have not been effective.[5] Its use for MS is approved in ten countries.[5][27] A 2012 review found no problems with tolerance, abuse or addiction.[28]

Adverse effects

A 2013 literature review found that exposure to marijuana had biologically-based physical, mental, behavioral and social health consequences and was "associated with diseases of the liver (particularly with co-existing hepatitis C), lungs, heart, and vasculature".[29] There is insufficient data to draw strong conclusions about the safety of medical cannabis, although short-term use is associated with minor adverse effects such as dizziness. Although supporters of medical cannabis say that it is safe,[30] further research is required to assess the long-term safety of its use.[6][31] The opinion of the Food and Drug Administration and many scientists is that some of the many different cannabionoids included in cannabis can have medical value, but not as smoked cannabis and only with controlled and careful prescription and the same testing for safety and effect as other approved drugs, a process that normally takes about 10 to 15 years from start to commercial product.[32]

Methods of consumption

Some forms of medicinal cannabis.

Smoking is the means of administration of cannabis for many consumers,[36] and the most common method of medical cannabis consumption in the US as of 2013.[5] It is difficult to predict the pharmacological response to cannabis because concentration of cannabinoids varies widely as there are different ways of preparing cannabis for consumption (smoked, applied as oils, eaten, or drunk) and a lack of production controls.[5] The potential for adverse effects from smoke inhalation makes smoking a less viable option than oral preparations.[36]

Cannabis vaporizers have gained popularity because of the perception among users that less harmful chemicals are ingested when components are inhaled via aerosol rather than smoke.[5]

Cannabinoid medicines are available in pill form (dronabinol and nabilone) and liquid extracts formulated into an oromucosal spray (nabiximols).[5] Oral preparations are "problematic due to the uptake of cannabinoids into fatty tissue, from which they are released slowly, and the significant first-pass liver metabolism, which breaks down Δ9THC and contributes further to the variability of plasma concentrations".[36]

Cannabinoid compounds

Tetrahydrocannabinol (THC), or delta-9-tetrahydrocannabinol, was identified in the 1960s as the cannabinoid primarily responsible for the psychoactive effects of cannabis;[5] in the 1990s, after the discovery of the cannabinoid receptors CB1[1] and CB2, researchers began to study and better understand how cannabinoids acted on these receptors.[5] THC is associated – more than any other cannabinoid – with most of the pharmacologic effects of cannabis.[5]

Cannabidiol (CBD) is a major constituent of medical cannabis; it is a nonpsychotropic and how it works on brain receptors is not known.[5] CBD represents up to 40% of extracts of Cannabis sativa.[37] A 2007 review said CBD had shown potential to relieve convulsion, inflammation, cough, congestion and nausea, and to inhibit cancer cell growth.[38] Preliminary studies have also shown potential over psychiatric conditions such as anxiety, depression, and psychosis.[37] Because cannabidiol relieves the aforementioned symptoms, cannabis strains with a high amount of CBD may benefit people with multiple sclerosis or frequent anxiety attacks.[26][38]

Cannabinol (CBN) is a product of THC and has mild psychtropic effects.[29]

Botanical strains

Cannabis sativa, Cannabis indica, and Cannabis ruderalis

Cannabis indica produces a higher level of cannabidiol (abbreviated CBD) relative to THC (the primary psychoactive component in medical and recreational cannabis). Cannabis sativa, on the other hand, produces a higher level of THC relative to CBD.[medical citation needed]

Medical use of sativa is associated with a cerebral high, and many patients experience stimulating effects. For this reason, sativa is often used for daytime treatment. It may cause more of a euphoric, "high" sensation, and tends to stimulate hunger, making it potentially useful to patients with eating disorders or anorexia. Sativa also exhibits a higher tendency to induce anxiety and paranoia, so patients prone to these effects may limit treatment with pure sativa, or choose hybrid strains.[medical citation needed]

Cannabis indica is associated with sedative effects and is often preferred for night time use, including for treatment of insomnia.[medical citation needed]Indica is also associated with a more "stoned" or meditative sensation than the euphoric, stimulating effects of sativa, possibly because of a higher CBD-to-THC ratio.[medical citation needed]

Many strains of cannabis are currently cultivated for medical use, including strains of both species in varying potencies, as well as hybrid strains designed to incorporate the benefits of both species. Hybrids commonly available can be heavily dominated by either Cannabis sativa or Cannabis indica, or relatively balanced, such as so-called "50/50" strains.[citation needed]

Pharmacologic products

In the U.S., the FDA has approved two oral cannabinoids for use as medicine: dronabinol and nabilone.[5] Dronabinol, synthetic THC, is listed as Schedule III, meaning it has some potential for dependence, and nabilone, a synthetic cannabinoid, is Schedule II, indicating high potential for side effects and addiction.[35]Nabiximols, an oromucosal spray derived from two strains of Cannabis sativa and containing THC and CBD,[35] is not approved in the U.S., but is approved in several European countries, Canada, and New Zealand as of 2013.[5]

Generic medication

Trade name(s)

Country

Licensed indications

Nabilone

Cesamet

U.S., Canada

Antiemetic (treatment of nausea or vomiting) associated with chemotherapy that has failed to respond adequately to conventional therapy[5]

Dronabinol

Marinol

U.S., Canada

Antiemetic (treatment of nausea or vomiting) associated with chemotherapy that has failed to respond adequately to conventional therapy[5]

As an antiemetic, these medications are usually used when conventional treatment for nausea and vomiting associated with cancer chemotherapy fail to work.[5]

Nabiximols is used for treatment of spasticity associated with MS when other therapies have not worked, and when an initial trial demonstrates "meaningful improvement".[5] Trials for FDA approval in the U.S. are underway.[5] It is also improved in several European countries for overactive bladder and vomiting.[35] When sold as Savitex as a mouth spray, the prescribed daily dose in Sweden delivers a maximum of 32.4 mg of THC and 30 mg of CBD; mild to moderate dizziness is common during the first few weeks.[39]

Relative to inhaled consumption, peak concentration of oral THC is delayed, and it may be difficult to determine optimal dosage because of variability in patient aborption.[5]

History

The use of cannabis, at least as fiber, has been shown to go back at least 10,000 years in Taiwan. "Dà má" (Pinyin pronunciation) is the Chinese expression for cannabis, the first character meaning "big" and the second character meaning "hemp."

Ancient

Cannabis, called má麻 (meaning "hemp; cannabis; numbness") or dàmá大麻 (with "big; great") in Chinese, was used in Taiwan for fiber starting about 10,000 years ago.[40] The botanist Li Hui-Lin wrote that in China, "The use of Cannabis in medicine was probably a very early development. Since ancient humans used hemp seed as food, it was quite natural for them to also discover the medicinal properties of the plant."[41] Emperor Shen-Nung, who was also a pharmacologist, wrote a book on treatment methods in 2737 BCE that included the medical benefits of cannabis. He recommended the substance for many ailments, including constipation, gout, rheumatism, and absent-mindedness.[42] Cannabis is one of the 50 "fundamental" herbs in traditional Chinese medicine.[43]

The Ebers Papyrus (ca. 1550 BCE) from Ancient Egypt has a prescription for medical marijuana applied directly for inflammation.

Surviving texts from ancient India confirm that cannabis' psychoactive properties were recognized, and doctors used it for treating a variety of illnesses and ailments, including insomnia, headaches, gastrointestinal disorders, and pain, including during childbirth.[46]

The Ancient Greeks used cannabis to dress wounds and sores on their horses,[47] and in humans, dried leaves of cannabis were used to treat nose bleeds, and cannabis seeds were used to expel tapeworms.[47]

Modern

An advertisement for cannabis americana distributed by a pharmacist in New York in 1917

An Irish physician, William Brooke O'Shaughnessy, is credited with introducing the therapeutic use of cannabis to Western medicine, to help treat muscle spasms, stomach cramps or general pain.[49]

Albert Lockhart and Manley West began studying in 1964 the health effects of traditional cannabis use in Jamaican communities. They developed, and in 1987 gained permission to market, the pharmaceutical Canasol: one of the first cannabis extracts.[50]

In the 1970s, a synthetic version of THC was produced and approved for use in the United States as the drug Marinol.[51]

Voters in eight US states showed their support for cannabis prescriptions or recommendations given by physicians between 1996 and 1999, going against policies of the federal government.[52] As of mid-2014, 23 states plus the District of Columbia have passed medical marijuana laws.[53]

Society and culture

Methods of acquisition

Medical marijuana dispensary

The method of obtaining medical cannabis varies by region and by legislation. In the US, most consumers grow their own or buy it from dispensaries in the states and the District of Columbia which permit the use of medical cannabis.[5]

The authors of report on a 2011 survey of medical cannabis users say that critics have suggested that some users "game the system" to obtain medical cannabis ostensibly for treatment of a condition, but then use it for nonmedical purposes – though the truth of this claim is hard to measure.[54] The report authors suggested rather that medical cannabis users occupied a "continuum" between medical and nonmedical use.[54]

Programs

As of 2011, 16 US states and the District of Columbia have public medical cannabis programs, but its use remains illegal by federal law.[27][dated info] In 1978 the US government created a program called the Compassionate Investigational New Drug program which dispenses cannabis cigarettes to 20 people with debilitating conditions[1] including glaucoma and a rare bone disease.[citation needed] The program was "closed to new candidates in 1991",[1] but as of 2013, allowed four people previously in the program to continue receiving medical cannabis.[citation needed]

Medical use of cannabis or preparation containing THC as the active substance is legalized in Austria, Belgium, Canada, Czech Republic, Finland, Israel, Netherlands, Spain, the UK and some states in the US, although it is illegal under US federal law.

Cannabis is in Schedule IV of the United Nations' Single Convention on Narcotic Drugs, making it subject to special restrictions. Article 2 provides for the following, in reference to Schedule IV drugs:[57]

A Party shall, if in its opinion the prevailing conditions in its country render it the most appropriate means of protecting the public health and welfare, prohibit the production, manufacture, export and import of, trade in, possession or use of any such drug except for amounts which may be necessary for medical and scientific research only, including clinical trials therewith to be conducted under or subject to the direct supervision and control of the Party.

The convention thus allows countries to outlaw cannabis for all non-research purposes but lets nations choose to allow medical and scientific purposes if they believe total prohibition is not the most appropriate means of protecting health and welfare. The convention requires that states that permit the production or use of medical cannabis must operate a licensing system for all cultivators, manufacturers and distributors and ensure that the total cannabis market of the state shall not exceed that required "for medical and scientific purposes."[57]

A number of medical organizations have endorsed reclassification of marijuana to allow for further study. These include, but are not limited to:

Research

"Victoria", the United States' first legal medical marijuana plant grown by The Wo/Men's Alliance for Medical Marijuana.[citation needed]

The Schedule I classification of cannabis in the US makes the study of medical cannabis difficult.[5] Another issue for research is the habit to mix cannabis with tobacco or switch between tobacco and cannabis.

Anecdotal evidence and pre-clinical research has suggested that cannabis or cannabinoids may be beneficial for treating Huntington's disease or Parkinson's disease, but follow-up studies of people with these conditions has not produced good evidence of therapeutic potential.[65] A 2001 paper argued that cannabis had properties that made it potentially applicable to the treatment of amyotrophic lateral sclerosis, and on that basis research on this topic should be permitted, despite the legal difficulties of the time.[66]

A 2005 review and meta-analysis said that bipolar disorder was not well-controlled by existing medications and that there were "good pharmacological reasons" for thinking cannabis had therapeutic potential, making it a good candidate for further study.[67]

Cannabinoids have been proposed for the treatment of primary anorexia nervosa, but have no measurable beneficial effect.[68] The authors of a 2003 paper argued that cannabinoids might have useful future clinical applications in treating digestive diseases.[69] Laboratory experiments have shown that cannabinoids found in marijuana may have analgesic and anti-inflammatory effects.[70]

In 2014, the American Academy of Neurology have reviewed all available findings levering the use of marijuana to treat brain diseases. The result was that the scientific evidence is weak to cannabis in any form serves as medicines for curing or alleviating neurological disorders. For ease MS patients' stiffness by taking cannabis extract by mouth or as a spray, there is support. The academy published a new guidelines on the use of marijuana pills and sprays in the treatment of multiple sclerosis.[71]

Cancer

Cannabinoids have been shown to exhibit some anti-cancer effects in laboratory experiments although there has been little research into their use as a cancer treatment in people.[72] Laboratory experiments have suggested that cannabis and cannabinoids have anticarcinogenic, antitumor and anticancer effects,[73] including a potential effect on breast and lung cancer cells.[70] The National Cancer Institute reports that as of November 2013[update] there have been no trials on the use of cannabis to treat cancer in people, and only one small trial using delta-9-THC.[74] Although there is ongoing research, claims that there is evidence showing that cannabis cures cancer are, according to Cancer Research UK, "highly misleading", and prevalent on the internet.[75]

There is no firm evidence that cannabis helps reduce the risk of getting cancer; whether it increases the risk is difficult to establish, since most users combine its use with tobacco smoking, and this complicates research.[75]

Dementia

Cannabinoids have been proposed as having the potential for lessening the effects of Alzheimer's disease.[76] A 2012 review of the effect of cannabinoids on brain ageing found that "clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing".[77] A 2009 Cochrane review said that the "one small randomized controlled trial [that] assessed the efficacy of cannabinoids in the treatment of dementia ... [had] ... poorly presented results and did not provide sufficient data to draw any useful conclusions".[78]

Diabetes

There is emerging evidence that cannabidiol may help slow cell damage in diabetes mellitus type 1.[79] There is a lack of meaningful evidence of the effects of medical cannabis use on people with diabetes; a 2010 review concluded that "the potential risks and benefits for diabetic patients remain unquantified at the present time".[80]

Epilepsy

A 2012 Cochrane review said there is not enough evidence to draw conclusions about the safety or efficacy of cannabinoids in the treatment of epilepsy.[81] There have been few studies of the anticonvulsive properties of CBD and epileptic disorders. The major reasons for the lack of clinical research have been the introduction of new synthetic and more stable pharmaceutical anticonvulsants, the recognition of important adverse effects and the legal restriction to the use of cannabis-derived medicines.[82] Epidiolex, a cannabis-based product developed by GW Pharmaceuticals for experimental treatment of epilepsy, will undergo stage-two trials in the US in 2014.[83]

Glaucoma

The American Glaucoma Society noted that while cannabis can help lower intraocular pressure, it recommended against its use because of "its side effects and short duration of action, coupled with a lack of evidence that it use alters the course of glaucoma."[84] As of 2008 relatively little research had been done concerning effects of cannabinoids on the eye.[85]

Tourette syndrome

A 2007 review of the history of medical cannabis said cannabinoids showed potential therapeutic value in treating Tourette syndrome (TS).[86] A 2005 review said that controlled research on treating TS with Marinol showed the patients taking the pill had a beneficial response without serious adverse effects;[87] a 2000 review said other studies had shown that cannabis "has no effects on tics and increases the individuals inner tension".[88]

A 2009 Cochrane review examined the two controlled trials to date using cannabinoids of any preparation type for the treatment of tics or TS (Muller-Vahl 2002, and Muller-Vahl 2003). Both trials compared delta-9-THC; 28 patients were included in the two studies (8 individuals participated in both studies).[36] Both studies reported a positive effect on tics, but "the improvements in tic frequency and severity were small and were only detected by some of the outcome measures".[36] The sample size was small and a high number of individuals either dropped out of the study or were excluded.[36] The original Muller-Vahl studies reported individuals who remained in the study; patients may drop out when adverse effects are too high or efficacy is not evident.[36] The authors of the original studies acknowledged few significant results after Bonferroni correction.[36]

Cannabinoid medication might be useful in the treatment of the symptoms in patients with TS,[36] but the 2009 review found that the two relevant studies of cannibinoids in treating tics had attrition bias, and that there was "not enough evidence to support the use of cannabinoids in treating tics and obsessive compulsive behaviour in people with Tourette's syndrome".[36]

^Washington, Tabitha A.; Brown, Khalilah M.; Fanciullo, Gilbert J. (2012). "Chapter 31: Medical Cannabis". Pain. Oxford University Press. p. 165. ISBN978-0-19-994274-9. "Proponents of medical cannabis site its safety, but there studies in later years that support that smoking of marijuana is associated with risk for dependence and that THC alters the structures of cells in the brain"

^ abUS patent 6630507, Aidan J. Hampson; Iulius Axelrod & Maurizio Grimaldi, "Cannabinoids as antioxidants and neuroprotectants", issued 2003-10-07, assigned to The United States of America as represented by the Department of Health and Human Services